Process for production of piperidine derivatives

ABSTRACT

The present invention relates to a process for preparing piperidine derivative compounds of the formulae: 
                 
 
wherein
         n is 0 or 1;   R 1  is hydrogen or hydroxy;
           R 2  is hydrogen;   or, when n is 0, R 1  and R 2  taken together form a second bond between the carbon atoms bearing R 1  and R 2 , provided that when n is 1, R 1  and R 2  are each hydrogen;   R 3  is —COOH or —COOR 4 ;   R 4  is an alkyl or aryl moiety;   A, B, and D are the substituents of their rings, each of which may be different or the same, and are selected from the group consisting of hydrogen, halogens, alkyl, hydroxy, alkoxy, and other substituents,
 
The process comprises providing a regiosomer of the following formula: 
                 
 
wherein
   
           Z is —CG 1 G 2 G 3 , 
                 
   m is an integer from 1 to 6;   Q and Y are the same or different and are selected from the group consisting of O, S, and NR 5 ;   G 1 , G 2 , and G 3  are the same or different and are selected from the group consisting of OR 8 , SR 8 , and NR 8 R 9 ;   R 6  and R 7  are the same or different and are selected from the group consisting of hydrogen, an alkyl moiety, an aryl moiety, OR 8 , SR 8 , and NR 8 R 9 ; and   R 5 , R 8 , and R 9  are the same or different and are selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety
 
and converting the regioisomer to the piperidine derivative compound with a piperidine compound.

This is a continuation of U.S. patent application Ser. No. 09/634,983,filed Aug. 9, 2000 now U.S. Pat. No. 6,444,824, which is a division ofU.S. patent application Ser. No. 08/576,068, filed Dec. 21, 1995, nowU.S. Pat. No. 6,153,754, which are hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to processes for the production ofpiperidine derivatives.

BACKGROUND OF THE INVENTION

Terfenadine,1-(p-tert-butylphenyl)-4-[4′-(α-hydroxydiphenylmethyl)-1′-piperidinyl]-butanolis a non-sedating anti-histamine. It is reported to be a specificH¹-receptor antagonist that is also devoid of any anticholingeric,anti-serotoninergic, and anti-adrenergic effects both in vitro and invivo. See D. McTavish, K. L. Goa, M. Ferrill, Drugs, 1990, 39, 552; C.R. Kingsolving, N. L. Monroe, A. A. Carr, Pharmacologist, 1973, 15, 221;J. K. Woodward, N. L. Munro, Arzneim-Forsch, 1982, 32, 1154; K. V. Mann,K. J. Tietze, Clin. Pharm. 1989, 6, 331. A great deal of effort has beenmade investigating structure-activity relationships of terfenadineanalogs, and this is reflected in the large number of U.S. patentsdisclosing this compound and related structures as follows:

-   -   U.S. Pat. No. 3,687,956 to Zivkovic    -   U.S. Pat. No. 3,806,526 to Carr, et. al.    -   U.S. Pat. No. 3,829,433 to Carr, et. al.    -   U.S. Pat. No. 3,862,173 to Carr, et. al.    -   U.S. Pat. No. 3,878,217 to Carr, et. al.    -   U.S. Pat. No. 3,922,276 to Duncan, et. al.    -   U.S. Pat. No. 3,931,197 to Carr, et. al.    -   U.S. Pat. No. 3,941,795 to Carr, et. al.    -   U.S. Pat. No. 3,946,022 to Carr, et. al.    -   U.S. Pat. No. 3,956,296 to Duncan, et. al.    -   U.S. Pat. No. 3,965,257 to Carr, et. al.    -   U.S. Pat. No. 4,742,175 to Fawcett, et. al.

In animal and human metabolic studies, terfenadine has been shown toundergo extensive hepatic first-pass metabolism, and after usual dosagesit cannot be detected in plasma unless very sensitive assays are used. Aspecific hepatic cytochrome P-450 enzyme converts terfenadine to themajor metabolite4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]1-hydroxybutyl]-α-α-dimethylphenylaceticacid, also known as terfenadine carboxylic acid metabolite. Thismetabolite can be readily detected in plasma and is considered to be theactive form of orally administered terfenadine.

Side effects reported with terfenadine are cardiac arrhythmias(ventricular tachyarrhythmias, torsades de points, ventricularfibrillation), sedation, GI distress, dry mouth, constipation and/ordiarrhea. The most serious of these, and potentially life threatening,are cardiac arrhythmias, which are related to terfenadine's ability toprolong the cardiac QT interval, and are only reported in patientsadministered terfenadine with liver disease or who also take theantifungal drug ketoconazole or the antibiotic erythromycin. As a resultof these adverse events, the FDA, in 1992, required terfenadine toinclude a warning label. Although OTC formulations of terfenadine arepurportedly being developed, the potentially serious side effects seenin some patients will be a significant obstacle for regulatory approval.

Since cardiac side effects of terfenadine have been reported in patientswith impaired liver function, as well as in patients also takingantibiotics known to suppress hepatic enzyme function, it was speculatedthat the cardiac side effects were due to accumulation of terfenadineand not due to accumulation of terfenadine carboxylic acid metabolite.Patch clamp studies in isolated feline ventricular myocytes support thecontention that terfenadine, and not the carboxylic acid metabolite, isresponsible for cardiac side effects. At a concentration of 1 μM,terfenadine caused a greater than 90% inhibition of the delayedrectifier potassium current. At concentrations up to 5 μM, theterfenadine carboxylic acid metabolite had no significant effect on thepotassium current in this assay (See R. L. Woosley, Y. Chen, J. P.Frieman, and R. A. Gillis, JAMA 1993, 269, 1532). Since inhibition ofion transport has been linked to cardiac abnormalities such asarrhythmias, these results indicate that terfenadine carboxylic acid islikely not liable to cause cardiac arrhythmias, at dose levels at whichthere is a distinct risk of such a side effect being caused byterfenadine itself.

Carebastine,4-[4-[4-(diphenylmethoxy)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylphenylaceticacid, is the carboxylic acid metabolite of ebastine,1-(p-tert-butylphenyl)-4-[4′-(α-diphenylmethoxy)-1′-piperidinyl]-butanol.Both compounds possess potent selective histamine H₁-receptor blockingand calcium antagonist properties and should prove useful in thetreatment of a variety of respiratory, allergic, and cardiovasculardisease states.

These compounds relax bronchial and vascular smooth muscle in vitro andin vivo and inhibit the constrictor influence of noradrenaline,potassium ions, and various other agonist drugs. The compounds alsoinhibit responses of intestinal and tracheal preparations to histamine,acetylcholine, and barium chloride and block the bronchoconstrictioninduced by histamine aerosol in guinea pigs in doses less than 1 mg/kganimal body weight administered orally. They also possessantianaphylactin properties in the rat, inhibit the skin lesions to avariety of anaphylactic mediators (histamine, 5-hydroxytryptamine,bradykinin, LCD₄, etc.), and antagonize the Schultz-Dale response in thesensitive guinea-pig.

Piperidine derivatives related to the terfenadine carboxylic acidmetabolite are disclosed in the following U.S. patents:

-   -   U.S. Pat. No. 4,254,129 to Carr, et. al.    -   U.S. Pat. No. 4,254,130 to Carr, et. al.    -   U.S. Pat. No. 4,285,957 to Carr, et. al.    -   U.S. Pat. No. 4,285,958 to Carr, et. al.        In these patents,        4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic        acid and related compounds are prepared by alkylation of a        substituted piperidine derivative of the formula:        with an ω-haloalkyl substituted phenyl ketone of the formula:        wherein the substituents halo, R¹, R², n, Z, and R⁶ are        described in column 6 of U.S. Pat. No. 4,254,130.

In similar fashion, U.S. Pat. No. 4,550,116 to Soto et al. describespreparation of piperidine derivatives related to carebastine by reactingthe ω-haloalkyl substituted phenyl ketone with a substitutedhydroxypiperidine derivative of the formula:

U.S. Pat. No. 4,254,130 indicates that ω-haloalkyl substituted phenylketones, wherein Z is hydrogen, are prepared by reacting an appropriatestraight or branched lower alkyl C₁₋₆ ester of α-α-dimethylphenylaceticacid with a compound of the following formula:

under the general conditions of a Friedel-Crafts acylation, wherein haloand m are described in column 11 of U.S. Pat. No. 4,254,129. Thereaction is carried out in carbon disulfide as the preferred solvent.

Other procedures for producing terfenadine carboxylic acid metaboliteare disclosed in PCT Application Nos. WO95/00482, WO94/03170, andWO95/00480.

The present invention is directed toward an improved process forpreparation of terfenadine carboxylic acid metabolite and carebastine.

SUMMARY OF THE INVENTION

The present invention relates to processes for preparing piperidinederivative compounds of the formulae:

wherein

-   -   n is 0 or 1;    -   R¹ is hydrogen or hydroxy;    -   R² is hydrogen;        or, when n is 0, R¹ and R² taken together form a second bond        between the carbon atoms bearing R¹ and R², provided that when n        is 1, R¹ and R² are each hydrogen;    -   R³ is —COOH or —COOR⁴;    -   R⁴ is an alkyl or aryl moiety;    -   A, B, and D are the substituents of their rings, each of which        may be different or the same, and are selected from the group        consisting of hydrogen, halogens, alkyl, hydroxy, alkoxy, and        other substituents        or a salt thereof. The piperidine derivative compound is        prepared by providing a regioisomer having the following        formula:        wherein    -   m is an integer from 1 to 6;    -   Q and Y are the same or different and are selected from the        group consisting of O, S, and NR⁵;    -   G¹, G², and G³ are the same or different and are selected from        the group consisting of OR⁸, SR⁸, and NR⁸R⁹;    -   R⁶ and R⁷ are the same or different and are selected from the        group consisting of hydrogen, an alkyl moiety, an aryl moiety,        OR⁸, SR⁸, and NR⁸R⁹; and    -   R⁵, R⁸, and R⁹ are the same or different and are selected from        the group consisting of hydrogen, an alkyl moiety, and an aryl        moiety.        The regioisomer is then converted to the piperidine derivative        having a keto group with a piperidine compound.

The invention further relates to a regioisomer having the formula:

The present invention is also directed to processes for preparing aregioisomer having the formula:

In one aspect of the invention, the process for preparing theregioisomer includes acylating an α,α-disubstituted-methylbenzenederivative having the formula:

wherein

-   -   X¹ is a halogen, trialkyl or triaryl tin, trialkyl or triaryl        borate, alkylhalo silicon, trialkyl silicon, a substituted        sulfonic ester, or substituents useful in organometallic        coupling resctions        with a compound having the formula:        wherein    -   X² is a halogen; an alkali metal oxide; a moiety having the        formula —OR¹⁰; a moiety having the formula —SR¹⁰; or an amine;        and    -   R¹⁰ is selected from the group consisting of hydrogen, an alkyl        moiety, and an aryl moiety        under conditions effective to produce the regioisomer.

In another aspect of the present invention, the process for preparingthe regioisomer includes reacting a 4-(α,α-disubstituted)-toluic acidderivative having the formula:

wherein

-   -   X² is hydrogen; a halogen; an alkali metal oxide; a moiety        having the formula —OR¹⁰; a moiety having the formula —SR¹⁰; or        an amine; and    -   R¹⁰ is selected from the group consisting of hydrogen, an alkyl        moiety, and an aryl moiety        with a compound having the formula:        wherein    -   X¹ is a halogen, trialkyl or triaryl tin, trialkyl or triaryl        borate, alkylhalo silicon, trialkyl silicon, a substituted        sulfonic ester, or substituents useful in organometallic        coupling reactions        under conditions effective to produce the regioisomer.

In yet another aspect of the invention, the process of preparing aregioisomer includes providing an α,α-diunsubstituted regioisomerprecursor having the formula:

and methylating the α,α-diunsubstituted regioisomer precursor underconditions effective to produce the regioisomer.

The present invention is also directed to anα,α-disubstituted-methylbenzene derivative having the formula:

and to an α,α-diunsubstituted-methylbenzene derivative having theformula:

The invention further relates to an oxobutyl derivative having theformula:

as well as to piperidine derivative precursors having the formulae:

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for preparing piperidinederivative compounds having the formulae:

wherein

-   -   n is 0 or 1;    -   R¹ is hydrogen or hydroxy;    -   R² is hydrogen;        or, when n is 0, R¹ and R² taken together form a second bond        between the carbon atoms bearing R¹ and R², provided that when n        is 1, R¹ and R² are each hydrogen;    -   R³ is —COOH or —COOR⁴;    -   R⁴ is an alkyl or aryl moiety;    -   A, B, and D are the substituents of their rings, each of which        may be different or the same, and are selected from the group        consisting of hydrogen, halogens, alkyl, hydroxy, alkoxy, and        other substituents or a salt thereof.

These piperidine derivative compounds may be in the form of4-diphenylmethylpiperidine derivatives represented by the followingformulae:

where A, B, D, and R³ are defined above. The piperidine derivativecompounds also include 4-(hydroxydiphenylmethyl)piperidine derivativesaccording to the following formulae:

where A, B, D, and R³ are defined above. Another useful class ofpiperidine derivative compounds are 4-diphenylmethylenepiperidinederivatives in accordance with the following formulae:

where A, B, D, and R³ are defined above.

Another useful class of piperidine derivative compounds are4-diphenylmethoxypiperidine derivatives having the following formulae:

where A, B, D, and R³ are defined above.

Examples of R⁴ are substituted or unsubstituted, straight or branchedalkyl groups, including methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, benzyl, and4-methylbenzyl groups and substituted or unsubstituted aryl groups,including phenyl, tolyl, and xylyl groups.

Illustrative examples of compounds prepared by the process of thepresent invention are as follows:

-   4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic    acid;-   4-[4-[4-(diphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic    acid;-   4-[4-[4-(diphenylmethylene)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic    acid;-   4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethyl-3-hydroxybenzeneacetic    acid;-   4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethyl-2-hydroxybenzeneacetic    acid;-   4-[4-[4-(diphenylmethylene)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethyl-3-hydroxybenzeneacetic    acid;-   4-[4-[4-(diphenylmethylene)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic    acid;-   ethyl    4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetate;-   n-pentyl    4-[4-[4-(diphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetate;-   ethyl    4-[4-[4-(diphenylmethylene)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetate;-   methyl    4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetate;-   ethyl    4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethyl-(3-hydroxybenzene)acetate;-   n-propyl    4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethyl-(2-hydroxybenzene)acetate;-   n-hexyl    4-[4-[4-(diphenylmethylene)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethyl-(3-hydroxybenzene)acetate;-   ethyl    4-[4-[4-(diphenylmethylene)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetate;-   4-[4-[4-(diphenylmethoxy)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic    acid;-   4-[4-[4-(diphenylmethoxy)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethyl-3-hydroxybenzeneacetic    acid;-   4-[4-[4-(diphenylmethoxy)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethyl-2-hydroxybenzeneacetic    acid;-   4-[4-[4-(diphenylmethoxy)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethyl-3-hydroxybenzeneacetic    acid;-   4-[4-[4-(diphenylmethoxy)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic    acid;-   n-pentyl    4-[4-[4-(diphenylmethoxy)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetate;-   ethyl    4-[4-[4-(diphenylmethoxy)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetate;-   ethyl    4-[4-[4-(diphenylmethoxy)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethyl-(3-hydroxybenzene)acetate;-   n-propyl    4-[4-[4-(diphenylmethoxy)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethyl-(2-hydroxybenzene)acetate;-   n-hexyl    4-[4-[4-(diphenylmethoxy)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethyl-(3-hydroxybenzene)acetate;    and-   ethyl    4-[4-[4-(diphenylmethoxy)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetate.    Particularly preferred are compounds of the formulae:

Optionally, both diphenyl groups from the piperidine compound may bealkyl (e.g., methyl) substituted at the position para to the methylene,such as

The compounds prepared by the methods of the present invention can bepharmaceutically acceptable salts in the form of inorganic or organicacid or base addition salts of the above compounds. Suitable inorganicacids are, for example, hydrochloric, hydrobromic, sulfuric, andphosphoric acids. Suitable organic acids include carboxylic acids, suchas, acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic,fumaric, malic, tartaric, citric, cyclamic, ascorbic, maleic,hydroxymaleic, dihydroxymateic, benzoic, phenylacetic, 4-aminobenzoic,anthranilic, cinnamic, salicylic, 4-aminosalicylic, 2-phenoxybenzoic,2-acetoxybenzoic, and mandelic acid. Sulfonic acids, such as,methanesulfonic, ethanesulfonic, and β-hydroxyethane-sulfonic acid arealso suitable acids. Non-toxic salts of the compounds of theabove-identified formulae formed with inorganic and organic basesinclude, for example, those alkali metals, such as, sodium, potassium,and lithium, alkaline earth metals, for example, calcium and magnesium,light metals of group IIIA, for example, aluminum, organic amines, suchas, primary, secondary, or tertiary amines, for example,cyclohexylamine, ethylamine, pyridine, methylaminoethanol, andpiperazine. These salts are prepared by conventional means, for example,by treating the piperidine derivative compounds of the formulae:

where A, B, D, n, R¹, R², and R³ are defined above, with an appropriateacid or base.

The piperidine derivative compounds prepared by the methods of thepresent invention can be utilized as the biologically active componentsin pharmaceutical compositions. These compounds are useful asantihistamines, antiallergy agents, and bronchodilators. They may beadministered alone or with suitable pharmaceutical carriers, and can bein solid or liquid form such as, tablets, capsules, powders, solutions,suspensions, or emulsions.

The compounds prepared by the methods of this invention can beadministered orally, parenterally, for example, subcutaneously,intravenously, intramuscularly, intraperitoneally, by intranasalinstillation or by application to mucous membranes, such as, that of thenose, throat, and bronchial tubes. Such application to mucous membranescan be achieved with an aerosol spray containing small particles of acompound of this invention in a spray or dry powder form.

The quantity of the compound administered will vary depending on thepatient and the mode of administration and can be any effective amount.The quantity of the compound administered may vary over a wide range toprovide in a unit dosage an effective amount of from about 0.01 to 20mg/kg of body weight of the patient per day to achieve the desiredeffect. For example, the desired antihistamine, antiallergy, andbronchodilator effects can be obtained by consumption of a unit dosageform such as a tablet containing 1 to 50 mg of the compound of thepresent invention taken 1 to 4 times daily.

The solid unit dosage forms can be of the conventional type. This solidform can be a capsule, such as an ordinary gelatin type containing thecompound of the present invention and a carrier, for example, lubricantsand inert fillers such as, lactose, sucrose, or cornstarch. In anotherembodiment, these compounds are tableted with conventional tablet basessuch as lactose, sucrose, or cornstarch in combination with binders likeacacia, cornstarch, or gelatin, disintegrating agents such as,cornstarch, potato starch, or alginic acid, and a lubricant like stearicacid or magnesium stearate.

The compounds prepared according to this invention may also beadministered in injectable dosages by solution or suspension of thecompounds of the present invention in a physiologically acceptablediluent with a pharmaceutical carrier. Such carriers include sterileliquids such as water and oils, with or without the addition of asurfactant and other pharmaceutically acceptable adjuvants. Illustrativeoils are those of petroleum, animal, vegetable, or synthetic origin, forexample, peanut oil, soybean oil, or mineral oil. In general, water,saline, aqueous dextrose and related sugar solution, and glycols suchas. propylene glycol or polyethylene glycol, are preferred liquidcarriers, particularly for injectable solutions.

For use as aerosols, the compounds in solution or suspension may bepackaged in a pressurized aerosol container together with suitablepropellants, for example, hydrocarbon propellants like propane, butane.or isobutane with conventional adjuvants. These compounds may beadministered in a non-pressurized form, such as in a nebulizer oratomizer.

The compounds made according to the present invention can be used totreat warm blooded animals, birds, and mammals. Examples of such beingsinclude humans, cats, dogs, horses, sheep, cows, pigs, lambs, rats,mice, and guinea pigs.

According to one aspect of the present invention, the piperidinederivative compounds are prepared by providing a regioisomer of thefollowing formula:

and converting the regioisomer to the piperidine derivative compounds ofthe invention having a keto group with a piperidine compound.

The resulting piperidine derivative compounds with a keto group can thenbe converted by reduction to the above-described piperidine compoundswith a hydroxyl group.

A is the substituents of its ring, each of which may be different or thesame and is selected from the group consisting of hydrogen, halogens,alkyl, hydroxy, alkoxy, or other substituents.

Z can be a carbon atom to which are bonded three electron rich groups,such as moieties having the formula CG¹G²G³. G¹, G², and G³ can be thesame or different and are illustratively selected from the groupconsisting of OR⁸, SR⁸, and NR⁸R⁹, where R⁸ and R⁹ are the same ordifferent and can be hydrogen; an alkyl moiety, including substituted orunsubstituted, branched or straight-chain alkyl moieties, such asmethyl, ethyl, n-propyl. isopropyl, n-butyl, sec-butyl, tert-butyl,n-pentyl, neopentyl, n-hexyl, benzyl, and 4-methylbenzyl, preferablyhaving from 1 to 7 carbon atoms; or an aryl moiety, includingsubstituted or unsubstituted aryl moieties, such as phenyl, tolyl, andxylyl. Examples of such a Z include triethoxymethyl or trimethoxymethylmoieties.

Z can also be a heterocyclic moiety having the formulae:

where m is an integer from 1 to 6 and Q and Y are independently oxygen,sulfur, or a substituted or unsubstituted amine having the formula NR⁵.R⁵ can be hydrogen; an alkyl moiety, including substituted orunsubstituted, branched or straight-chain alkyl moieties, such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl,n-pentyl, neopentyl, n-hexyl, benzyl, and 4-methylbenzyl, preferablyhaving from 1 to 7 carbon atoms; or an aryl moiety, includingsubstituted or unsubstituted aryl moieties, such as phenyl, tolyl, andxylyl groups. It is to be understood that R⁶ and R⁷, the twosubstituents bonded to each methylene (i.e. CH₂ group), of which thereare m in the above formulae, are independently selected from each other.In addition, it is to be understood that R⁶ groups and R⁷ groups on onemethylene can be the same or different than those on other methylenes.Each R⁶ and each R⁷ can be hydrogen; an alkyl moiety, includingsubstituted or unsubstituted, branched or straight-chain alkyl moieties,such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,tert-butyl, n-pentyl, neopentyl, n-hexyl, 2-methylpentyl, cyclohexyl,benzyl, and 4-methylbenzyl, preferably having from 1 to 7 carbon atoms;an aryl moiety, including substituted or unsubstituted aryl moieties,such as phenyl, tolyl, xylyl, and naphthyl; or a moiety having theformulae OR⁸, SR⁸, or NR⁸R⁹, where R⁸ and R⁹ are defined as they wereabove where Z had the formula CG¹G²G³. Preferred examples of Z includeisoxazoline moieties having the formula:

wherein R⁶, R⁷, R¹², and R¹³ are the same or different and can behydrogen; an alkyl moiety, including substituted or unsubstituted,branched or straight-chain alkyl moieties, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl,neopentyl, n-hexyl, 2-methylpentyl, cyclohexyl, benzyl, and4-methylbenzyl, preferably having from 1 to 7 carbon atoms; an arylmoiety, including substituted or unsubstituted aryl moieties, such asphenyl, tolyl, xylyl, and naphthyl; or a moiety having the formulae OR⁸,SR⁸, or NR⁸R⁹, where R⁸ and R⁹ are as defined as they were above.Preferably, m is 2, and R¹² and R¹³ are hydrogen. More preferably, R¹²and R¹³ are hydrogen, and R⁶ and R⁷ are each an alkyl moiety having from1 to 7 carbon atoms. Most preferably, Z is 4,4-dimethylisoxazolin-2-yl,where each of R¹² and R¹³ is hydrogen and R⁶ and R⁷ is methyl.

A variety of methods can be used to provide these regioisomers.

Process For Producing The Regioisomer

In one embodiment of the present invention, the regioisomer is producedby acylating an α,α-disubstituted-methylbenzene derivative having theformula:

with a compound having the formula:

under conditions effective to produce the regioisomer having theformula:

In this embodiment, the acylation agent is a cyclopropyl derivative.

In another embodiment of the present invention, the acylation agent is a4-(α,α-disubstituted)-toluic acid derivative. In this embodiment, theregioisomer is produced by reacting a 4-(α,α-disubstituted)-toluic acidderivative having the formula:

with a compound having the formula:

under conditions effective to acylate the compound, producing theregioisomer.

Irrespective of whether the regioisomer is produced using the processemploying a cyclopropyl derivative acylation agent or the processemploying a 4-(α,α-disubstituted)-toluic acid derivative acylationagent, X¹ can be a halogen; trialkyl or triaryl tin; trialkyl or triarylborate; alkylhalo silicon; trialkyl silicon; or a substituted sulfonicester, such as tosylate, mesylate, or triflate, with any alkyl groupsbeing straight or branched and preferably having 1 to 4 carbon atoms.Alternatively, X¹ can be a substituent useful in organometallic couplingreactions, including lithium or magnesium compounds derived from bromineor iodine. As used herein, alkylhalo silicon is a tetravalent siliconatom bonded to at least one halogen and at least one alkyl group. Theremaining silicon valency is bonded to either a second halogen or asecond alkyl. One particularly useful alkylhalo silicon has the formula—SiCH₃F₂.

X², in either embodiment, can be hydrogen; a halogen; an alkali metaloxide; a moiety having the formula —OR¹⁰; a moiety having the formula—SR¹⁰; or an amine. Suitable amines are those having the formula—NR¹⁰R¹¹ or —NR¹⁰(OR¹¹); saturated cyclic amines, such as those havingthe formulae:

or heteroaryl amines, such as imidazole, pyrazole, and the like. R¹⁰ andR¹¹ are the same or different and are selected from the group consistingof hydrogen; an alkyl moiety, including substituted or unsubstituted,branched or straight-chain alkyl moieties, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl,neopentyl, n-hexyl, benzyl, and 4-methylbenzyl, preferably having from 1to 7 carbon atoms; and an aryl moiety, including substituted orunsubstituted aryl moieties, such as phenyl, tolyl, and xylyl groups; pis an integer, preferably from 2 to 8.

In practicing the process employing a cyclopropyl derivative acylationagent, suitable acylation agents include cyclopropylcarboxylic acidhalides, alkali metal cyclopropylcarboxylic acid salts,cyclopropylcarboxylic acid esters, or cyclopropylcarboxylic acid amides.

Suitable cyclopropylcarboxylic acid halides includecyclopropylcarboxylic acid fluoride, cyclopropylcarboxylic acidchloride, and cyclopropylcarboxylic acid bromide. Where an alkali metalsalt of cyclopropylcarboxylic acid is employed as the acylation agent,suitable alkali metals include lithium, sodium, and potassium.

Cyclopropylcarboxylic acid amides can be N-unsubstituted amides, such ascyclopropylcarboxylic acid amide; an N-monosubstituted amide, such asN-methyl cyclopropylcarboxylic acid amide, N-ethyl cyclopropylcarboxylicacid amide, N-propyl cyclopropylcarboxylic acid amide, and N-hexylcyclopropylcarboxylic acid amide; or an N,N-disubstituted amide.Suitable N,N-disubstituted amides include N,N-dimethylcyclopropylcarboxylic acid amide, N-methyl-N-ethyl cyclopropylcarboxylicacid amide, N-methyl-N-propyl cyclopropylcarboxylic acid amide,N-methyl-N-hexyl cyclopropylcarboxylic acid amide, N,N-diethylcyclopropylcarboxylic acid amide, N-ethyl-N-propyl cyclopropylcarboxylicacid amide, N-ethyl-N-hexyl cyclopropylcarboxylic acid amide,N,N-dipropyl cyclopropylcarboxylic acid amide, N-propyl-N-hexylcyclopropylcarboxylic acid amide, and N,N-dihexyl cyclopropylcarboxylicacid amide. N,N-disubstituted cyclopropylcarboxylic acid amides havingthe formula —NR¹⁰(OR¹¹), such as N-methyl-N-methoxycyclopropylcarboxylic acid amide, N-methyl-N-ethoxycyclopropylcarboxylic acid amide, N-ethyl-N-methoxycyclopropylcarboxylic acid amide, and N-ethyl-N-ethoxycyclopropylcarboxylic acid amide, are particularly useful. SuitableN,N-disubstituted amides also include cyclic amides, such as cyclopropylcarboxylic acid morpholine amide, cyclopropyl carboxylic acid piperazineamide, cyclopropyl carboxylic acid imidazole amide, and cyclopropylcarboxylic acid pyrazole amide, as well as those having the formula:

where p is an integer, preferably from 2 to 8, examples of which includeN,N-ethylene cyclopropylcarboxylic acid amide, N,N-propylenecyclopropylcarboxylic acid amide, N,N-butylene cyclopropylcarboxylicacid amide, and N,N-pentylene cyclopropylcarboxylic acid amide.

Irrespective of whether the regioisomer is produced using the processemploying a cyclopropyl derivative acylation agent or the processemploying a 4-(α,α-disubstituted)-toluic acid derivative acylationagent, the acylation reactions are carried out in a suitable solvent inthe presence of an appropriate catalyst for about 1 to 120 hours and attemperatures of about −78° C. to the reflux temperature of the solvent.Suitable solvents for acylation include: hydrocarbon solvents, such asbenzene, toluene, xylene, or cyclohexane; halogenated hydrocarbons, suchas chlorobenzene, dichloroethane, methylene chloride, chloroform, orcarbon tetrachloride; carbon disulfide; dimethylformamide; etherealsolvents, like tetrahydrofuran and diethylether; or dioxane.

In practicing either of the above processes, a variety of catalysts maybe utilized when A is hydrogen. Suitable catalysts include palladiumcatalysts, like palladium chloride, palladium acetate,tetrakis(triphenylphosphine) palladium(0),dichlorobis(triphenylphosphine) palladium(II), orbenzylchlorobis(triphenylphosphine)palladium(II); or nickel-phosphinecatalysts. Acylation may also be carried out in the presence of addedlithium chloride or triphenylphosphine. The latter acylation reaction isknown in the art as organometallic cross-coupling reactions and areconducted by the general procedures of D. Milstein, et al., J. Org.Chem., 1979, 44, 1613; J. W. Labadie, et al., J. Org. Chem., 1983, 48,4634; C. Sahlberg, et al., Tetrahedron Letters, 1983, 24, 5137; D.Milstein, et al., J. Am. Chem. Soc., 1978, 100, 3636; and K. Tamao, etal., Tetrahedron, 1982, 38, 3347, all of which are hereby incorporatedby reference.

Where acylation is carried out using the process employing a cyclopropylderivative acylation agent, the reaction can also be promoted byaddition of an acylation promoter which, when reacted with themethylbenzene derivative, displaces X¹ from the benzene ring, forming areactive carbanion salt. One suitable acylation promoter is butyllithium, which is particularly effective when X² is an amine. When X² ischloride, preferred acylation promoters are magnesium metal ortetraalkyl tin. Acylation promoters, especially organometallics such asbutyl lithium, are highly reactive with carbonyl groups. For thisreason, the Z moiety is chosen to minimize reactivity of the carbon betato the benzene ring. In particular, when employing an acylationpromoter, Z moieties having the formula:

such as isoxazolidium groups, are preferred.

The α,α-disubstituted-methylbenzene derivative having the formula:

can be provided by reacting an α,α-diunsubstituted-methylbenzenederivative having the formula:

with a methylating agent under conditions effective to produce theα,α-disubstituted-methylbenzene derivative . The methylation reaction iscarried out in a suitable solvent and in the presence of a suitablenon-nucleophilic base, such as potassium t-butoxide, sodium hydride,lithium diisopropylamide (“LDA”), lithium hexamethyldisilazide(“LHMDS”). potassium hexamethyldidisilazide (“KHMDS”), sodium or lithiumtetramethylpiperidine, or related strong bases, for about 1 to about 120hours, at temperatures from about −78° C. to room temperature.Preferably, the reaction is conducted under an inert, dry atmosphere,such as N₂ or Ar gas, in an inert, dry solvent. Suitable solvents formethylation include: hydrocarbon solvents, such as benzene, toluene,xylene, or cyclohexane; halogenated hydrocarbons, such as chlorobenzene,dichloroethane, methylene chloride, or carbon tetrachloride; carbondisulfide; dimethylformamide; ethereal solvents, like tetrahydrofuran,t-butyl methyl ether, and diethylether; or dioxane. At least two molarequivalents and, preferably, between 2.1 and 3 molar equivalents ofmethylating agent are employed and added over the course of thereaction, either continuously or in two or more slugs. Suitablemethylating agents include iodomethane, bromomethane, chloromethane,dimethyl sulfate, and the like.

The α,α-diunsubstituted-methylbenzene derivatives having the formula:

can be prepared by reacting the correponding α,α-diunsubstitutedbenzylic acid of the formula:

with an appropriate aminoalkyl derivative having the formula:H₂N—(CR⁶R⁷)_(m)—Q—Hunder conditions effective to produce theα,α-diunsubstituted-methylbenzene derivative. This reaction is conductedin a suitable solvent for about 1 to about 120 hours and at atemperature ranging from 0° C. to the reflux temperature of the solvent.Suitable solvents for this reaction include: hydrocarbon solvents, suchas benzene, toluene, xylene, or cyclohexane; halogenated hydrocarbons,such as chlorobenzene, dichlorethane, methylene chloride, chloroform, orcarbon tetrachloride; carbon disulfide; dimethylformamide; etheralsolvents, like tetrahydrofuran and diethylether; or dioxane. Preferably,the solvent is maintained at reflux in an apparatus having a means forremoving water, such as a Dean-Stark trap. In many cases, it isadvantageous to convert the α,α-diunsubstituted-benzylic acid derivativeto the corresponding acid halide, such as by treatment with thionylchloride, prior to reaction with the aminoalkyl derivative.

Alternatively, the α,α-disubstituted-methylbenzene derivative having theformula:

can be prepared from the corresponding α,α-disubstituted-benzylic acidderivative having the formula:

by reacting the α,α-disubstituted-benzylic acid derivative with theabove aminoalkyl derivative under the conditions described above withrespect to the α,α-diunsubstituted-benzylic acid conversion.

The α,α-disubstituted-benzylic acid derivative used to prepare theα,α-disubstituted-methylbenzene derivative can be synthesized bymethylating the corresponding α,α-diunsubstituted-benzylic acidderivative. Conditions suitable to carry out this methylation are thesame as those described above with respect to methylation ofα,α-diunsubstituted-methylbenzene derivatives.

Where acylation is carried out with a 4-(α,α-disubstituted)-toluic acidderivative having the formula:

the 4-(α,α-disubstituted)-toluic acid derivative can be provided byreacting a 4-(α,α-diunsubstituted)-toluic acid derivative having theformula:

with a methylating agent under conditions effective to produce the4-(α,α-disubstituted)-toluic acid derivative. Suitable methylationconditions are the same as those described above. The4-(α,α-diunsubstituted)-toluic acid derivatives having the formula:

can be prepared by reacting the correponding4-(α-carboxy-α,α-diunsubstituted)-toluic acid derivative having theformula:

with an appropriate aminoalkyl derivative having the formula:H₂N—(CR⁶R⁷)_(m)—Q—Hunder conditions effective to produce the 4-(α,α-diunsubstituted)-toluicacid derivative. Conditions suitable to effect this reaction are thesame as those given above for reaction ofα,α-diunsubstituted-methylbenzene derivatives with aminoalkylderivatives.

Alternatively, the 4-(α,α-disubstituted)-toluic acid derivative havingthe formula:

can be prepared from the corresponding4-(α-carboxy-α,α-disubstituted)-toluic acid derivative having theformula:

by reacting the 4-(α-carboxy-α,α-disubstituted)-toluic acid derivativewith the above aminoalkyl derivative under the conditions describedabove with respect to the reaction of α,α-diunsubstituted-benzylic acidderivatives with aminoalkyl derivatives.

The 4-(α-carboxy-α,α-disubstituted)-toluic acid derivative used toprepare the 4-(α,α-disubstituted)-toluic acid derivative can besynthesized by methylating the corresponding4-(α-carboxy-α,α-diunsubstituted)-toluic acid derivative. Conditionssuitable for carrying out this methylation are the same as thosedescribed above with respect to methylation ofα,α-diunsubstituted-methylbenzene derivatives.

The regioisomer of the present invention having the formula:

can also be prepared from a corresponding α,α-diunsubstitutedregioisomer precursor having the formula:

by methylation using reagents and conditions described above withrespect to the methylation of α,α-diunsubstituted-methylbenzenederivatives. When employing this route, the α,α-diunsubstitutedregioisomer precursor is conveniently prepared from aα,α-diunsubstituted-methylbenzene derivative having the formula:

by acylating the α,α-diunsubstituted-methylbenzene derivative with anacylation agent having the formula:

under conditions effective to produce the α,α-diunsubstitutedregioisomer precursor. Acylation conditions suitable for this reactionare the same as those described above with respect to acylation ofα,α-disubstituted-methylbenzene derivatives.Process of Converting the Regioisomer to the Piperidine DerivativeHaving a Keto Group

Once the regioisomer is provided, it is then converted to the piperidinederivative with a piperidine compound.

In one aspect of the invention, the regioisomer having the formula:

is reacted with a piperidine compound having the formula:

R¹⁷ and R¹⁸ in the above formula can be the same or different and areselected from the group consisting of an alkyl moiety, includingsubstituted or unsubstituted, branched or straight-chain alkyl moieties,such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,tert-butyl, n-pentyl, neopentyl, n-hexyl, benzyl, and 4-methylbenzyl,preferably having from 1 to 7 carbon atoms; and an aryl moiety,including substituted or unsubstituted aryl moieties, such as phenyl,tolyl, and xylyl groups. Preferably, the reaction is conducted under aninert, dry atmosphere, such as nitrogen or argon, in an inert, drysolvent, at temperatures from about −50° C. to about the refluxtemperature of the solvent. Suitable solvents include hydrocarbonsolvents, such as benzene, toluene, xylene, or cyclohexane;dimethylformamide; ethereal solvents, like tetrahydrofuran, t-butylmethyl ether, and diethylether; or dioxane.

In another aspect of the present invention, conversion of theregioisomer to the piperidine derivative is effected by halogenating,hydroxylating, alkoxylating, or aryloxylating the regioisomer underconditions effective to form a first intermediate compound having theformula:

wherein X³ is a halogen or a hydroxy, alkoxy, or aryloxy moiety.

Suitable halogens include chlorine, bromine, and iodine. Suitableconditions for carrying out halogenating include reacting theregioisomer with a halogen nucleophile and a Lewis Acid. Thehalogenation reaction is carried out in a suitable solvent, optionallyin the presence of a catalytic amount of base, for about 0.5 to 24 hoursand a temperature of about −40 degrees C. to the reflux temperature ofthe solvent. Suitable halogen nucleophiles include sodium iodide, sodiumbromide, potassium iodide, potassium bromide, cesium iodide, cesiumbromide, trimethylsilyl iodide, manganese iodide, cerium iodide,magnesium bromide, magnesium iodide, magnesium carbonate, calciumbromide, and calcium iodide. Suitable Lewis Acids include siliconcompounds, such as trimethylsilyl chloride and trimethylsilyl iodide;aluminum compounds, such as aluminum chloride, trimethyl aluminum,diethyl aluminum chloride, ethyl aluminum dichloride, and diethylaluminum cyanide; magnesium salts; and boron salts. Suitable solventsfor the halogenation reaction include alcohols, such as methanol,ethanol, isopropanol, and various glycols; hydrocarbon solvents, suchas, benzene, toluene, xylene, or cyclohexane; ethereal solvents such asether, tetrahydrofuran, dioxane, or dimethoxyethane; or halogenatedhydrocarbons, such as, chlorobenzene, methylene chloride, carbontetrachloride, chloroform, or dichloroethane.

The halogenation reaction can be conducted in a mixture of organicsolvent and mineral acid, such as hydrochloric acid, hydrobromic acid,or hydroiodic acid. In this manner, in addition to decyclizing thecyclopropyl ring, the moiety herein referred to as Z is cleaved,yielding the first intermediate compounnd.

Alternatively, the above halogenation can comprise two separate steps.In the first step, the regioisomer of the present invention isdecyclized under conditions effective to produce an oxobutyl derivativehaving the formula:

Decyclizing can be effected with a halogen nucleophile and a Lewis Acidunder conditions described above. At this point, the oxobutyl derivativecan optionally be purified to remove excess decyclizing reagent. Theoxobutyl derivative is converted to the first intermediate compound bytreatment of the oxobutyl derivative with a mineral acid, such ashydrochloric acid, hydrobromic acid, or hydroiodic acid. It is preferredthat treatment with acid be effected separately from the decyclizing.Further, it is preferred that treatment with acid be effected onpurified oxobutyl derivative, rather than on oxobutyl derivativecontaminated with excess decyclizing agent.

As indicated above, the regioisomer can also be converted to theoxobutyl derivative by hydroxylation, alkoxylation, or aryloxylation. Insuch cases, X³ is OR¹⁹, where R¹⁹ can be hydrogen, an alkyl group, or anaryl group. Alkoxylation or aryloxylation is carried out by reacting theregioisomer with mineral acids in an solution of the appropriatealcohol, such as methanol when R¹⁹ is methyl, ethanol when R¹⁹ is ethyl,and phenol when R¹⁹ is phenyl. Hydroxylation can be effected by treatingthe regioisomer with mineral acids in an aqueous solution. Theintermediate hydroxy compound can then be converted to a sulfonateester, such as the tosylate or mesylate ester, by reaction with asulfonyl halide, such as p-toluenesulfonyl chloride or methanesulfonylchloride.

If desired, the acid group of the first intermediate compound can beesterified by techniques well known to those skilled in the art, such asby evaporating an alcoholic solution of the acid and a mineral acid,such as a methanolic, ethanolic, propanolic, or butanolic solution ofhydrochloric, hydrobromic, or hydroiodic acid, to dryness to form anester having the formula:

After halogenation, alkoxylation, or aryloxylation and optionalesterification, the first intermediate compound or ester thereof can bereacted with a piperidine compound of the formula:

under conditions effective to form the piperidine derivative compoundhaving a keto group of the formula:

This alkylation reaction is carried out in a suitable solvent preferablyin the presence of a base and, optionally, in the presence of acatalytic amount of potassium iodide for about 4 to 120 hours at atemperature of about 70° C. to the reflux temperature of the solvent.Suitable solvents for the alkylation reaction include alcohol solvents,such as, methanol, ethanol, isopropyl alcohol, or n-butanol; ketonesolvents, such as methyl isobutyl ketone and methyl ethyl ketone;hydrocarbon solvents, such as benzene, toluene, or xylene; halogenatedhydrocarbons, such as, chlorobenzene or methylene chloride; ordimethylformamide. Suitable bases for the alkylation reaction includeinorganic bases, for example, sodium bicarbonate, potassium carbonate,or potassium bicarbonate or organic bases, such as a trialkylamine, forexample, triethylamine or pyridine, or an excess of the piperidinecompound can be used. When the piperidine derivative is in the form ofan ester, it can be hydrolyzed to a carboxylic acid.

Piperidine derivative compounds of the present invention having n equalto 1 can also be prepared by the following alternative alkylationprocedure. Subsequent to halogenation and optional esterification, thefirst intermediate compound having the formula:

is reacted with 4-hydroxypiperidine in an organic solvent, such astoluene, dioxane, xylene, methyl ethyl ketone, methyl isobutyl ketone,or N,N-dimethylformamide, at a temperature between 80° and 140° C. andin the presence of an acid-binding agent, such as an alkali metalcarbonate or bicarbonate, to form an N-substituted hydroxypiperidinehaving the formula:

The N-substituted hydroxypiperidine is then reacted with adiphenylmonohalomethane having the formula:

wherein X⁴ is a halogen, under conditions effective to form thepiperidine derivative compound of the formula:

The reaction is preferably carried out in an inert organic solvent, forexample, toluene, xylene, dioxane, methyl isobutyl ketone, orN,N-dimethylformamide, at a temperature between 80° and 140° C. in thepresence of an acid-binding agent such as an alkali metal carbonate orbicarbonate. The diphenylmonohalomethanes can be obtained commercially,or they can be prepared by the methods known in the art, for example, byreaction of the corresponding diphenylmethanol with a phosphorous orthionyl chloride or bromide in an inert organic solvent. Thisalternative alkylation method is preferred when R³ in the firstintermediate compound is —COOH.

Irrespective of the alkylation procedure employed, when R³ is —COOalkyl,the alkylation reaction can be followed by base hydrolysis to convert R³substituents that are —COOalkyl groups to —COOH groups. Such basehydrolysis involves treatment of the piperidine derivative with aninorganic base, such as sodium hydroxide, in an aqueous lower alcoholsolvent, such as aqueous methanol, ethanol, isopropyl alcohol, orn-butanol, at reflux temperature for about ½ hour to 12 hours.

Piperidine compounds where n=0 and each of R¹ and R² is hydrogen orwhere n=0 and R¹ is hydroxy and R² is hydrogen are commerciallyavailable or may be prepared according to procedures well known in theart (e.g. F. J. McCarty, C. H. Tilford, M. G. Van Campen, J. Am. Chem.Soc., 1961, 26, 4084, which is hereby incorporated by reference).Piperidine compounds wherein n=0 and R¹ and R² form a second bondbetween the carbon atoms bearing R¹ and R² may be prepared bydehydration of the corresponding compound wherein R¹ is hydroxy byprocedures generally known in the art. Piperidine compounds wherein n=1and R¹ and R² are both hydrogen are prepared by condensation of anappropriately substituted diphenylmonohalomethane, such asdiphenylchloromethane, diphenylbromomethane, anddi(p-tolyl)chloromethane, with a 1-alkoxycarbonyl-4-hydroxypiperidine ina suitable solvent, such as toluene, xylene, dioxane, methylisobutylketone, or N,N-dimethylformamide. The reaction is conducted at atemperature between 80° C. and 140° C. and in the presence of a base,such as an alkali metal carbonate or bicarbonate. Following thereaction, hydrolysis with alkali metal hydroxide in an organic solvent,such as ethanol or isopropanol, at the boiling point of the solvent,yields the 4-(diarylmethoxy)-piperidine free base.

In yet another aspect of the present invention, the piperidinederivative compound is produced by decyclizing the regioisomer of thepresent invention under conditions effective to produce a oxobutylderivative compound having the formula:

Decyclization can be effected by reacting the regioisomer with a halogennucleophile and a Lewis Acid. Decyclization is carried out in a suitablesolvent, optionally in the presence of a catalytic amount of an optionalnucleophile, for about 0.5 to 24 hours and a temperature of about −40degrees C. to the reflux temperature of the solvent. Suitable halogen,Lewis Acids, and solvents include those which were discussed above inregard to halogenating the regioisomer.

The oxobutyl derivative compound is converted to a piperidine derivativeprecursor having the formula:

by reacting the oxobutyl derivative with a piperidine compound havingthe formula:

under conditions effective to form the piperidine derivative precursor.This alkylation reaction is carried out in a suitable solvent preferablyin the presence of a base and, optionally, in the presence of acatalytic amount of potassium iodide for about 4 to 120 hours at atemperature of about 70° C. to the reflux temperature of the solvent.Suitable solvents for the alkylation reaction include alcohol solvents,such as, methanol, ethanol, isopropyl alcohol, or n-butanol; ketonesolvents, such as, methyl isobutyl ketone and methyl ethyl ketone;hydrocarbon solvents, such as, benzene, toluene, or xylene; halogenatedhydrocarbons, such as, chlorobenzene or methylene chloride; ordimethylformamide. Suitable bases for the alkylation reaction includeinorganic bases, for example, sodium bicarbonate, potassium carbonate,or potassium bicarbonate or organic bases, such as a trialkylamine, forexample, triethylamine or pyridine, or an excess of the piperidinecompound can be used.

Alternatively, piperidine derivative precursors of the present inventionhaving n equal to 1 can also be prepared by reacting the oxobutylderivative having the formula:

with 4-hydroxypiperidine in an organic solvent, such as toluene,dioxane, xylene, methyl isobutyl ketone, or N,N-dimethylformamide, at atemperature between 80° and 140° C. and in the presence of anacid-binding agent, such as an alkali metal carbonate or bicarbonate, toform an N-substituted hydroxypiperidine having the formula:

The N-substituted hydroxypiperidine is then reacted with adiphenylmonohalomethane having the formula:

wherein X⁴ is a halogen, under conditions effective to form thepiperidine derivative precursor of the formula:

The reaction is preferably carried out in an inert organic solvent, forexample, toluene, xylene, dioxane, methyl isobutyl ketone, orN,N-dimethylformamide, at a temperature between 80° and 140° C. in thepresence of an acid-binding agent such as an alkali metal carbonate orbicarbonate.

Irrespective of the alkylation procedure employed, the piperidinederivative precursor is then converted to the piperidine derivativehaving the formula:

This conversion can be effected by treatment of the piperidinederivative precursor with a mineral acid, such as hydrochloric acid,hydrobromic acid, or hydroiodic acid in a suitable organic solvent, forabout 0.5 to 24 hours and a temperature of about −40 degrees C. to thereflux temperature of the solvent. Suitable solvents include alcohols,such as methanol, ethanol, isopropanol, and various glycols; hydrocarbonsolvents, such as, benzene, toluene, xylene, or cyclohexane; etherealsolvents such as ether, tetrahydrofuran, dioxane, or dimethoxyethane; orhalogenated hydrocarbons, such as, chlorobenzene, methylene chloride,carbon tetrachloride, chloroform, or dichloroethane. Alternatively, thisconversion can be effected in vivo by administering the piperidinederivative percursor to a subject, and permitting the subject tometabolize the piperidine derivative precursor to the piperidinederivative compound.

Piperidine derivative precursors of the present invention can be used totreat patients suffering from allergic reactions, such as asthma,allergic rhinitis, and other conditions which can be treated withpiperidine derivative compounds. Treatment includes administering to thepatient an effective amount of the piperidine derivative precursor. Theamounts and modes of administration are the same as those discussedabove for administration of piperidine derivative compounds.

Processes for Reduction of Keto Group in Piperidine Derivative Compoundsand Precursors

As discussed above, the process of the present invention is useful inproducing piperidine derivatives with either a keto group or a hydroxylgroup. Derivatives with keto groups can be converted to similarcompounds with hydroxyl groups by reduction reactions which are wellknown in the art.

Reduction can be carried out with sodium borohydride or potassiumborohydride in lower alcohol solvents, such as, methanol, ethanol,isopropyl alcohol, or n-butanol.

When lithium aluminum hydride or diborane are used as reducing agents,suitable solvents are ethers, for example, diethyl ether,tetrahydrofuran, or dioxane. These reduction reactions are carried outat temperatures ranging from about 0° C. to the reflux temperature ofthe solvent, and the reaction time varies from about 0.5 to 8 hours.

Catalytic reduction with hydrogen may also be employed using, forexample, Raney nickel, palladium, platinum, or rhodium catalysts inlower alcohol solvents, such as, methanol, ethanol, isopropyl alcohol,or n-butanol or acetic acid or their aqueous mixtures, or by the use ofaluminum isopropoxide in isopropyl alcohol. Reduction using sodiumborohydride is generally preferred over catalytic reduction when formingcarboxylic acids or esters.

The piperidine derivative containing a hydroxy group thus prepared canoptionally be separated into its enantiomerically pure components byconventional methods. For example, the racemic mixture of piperidinederivative enantiomers can be converted to a racemic mixture ofdiastereomers with a reactive chiral agent. The diastereomers are thenseparated by, for example, recrystallization or chromatography, and thepure enantiomer is recovered by cleaving the reactive chiral agent.Alternatively, the racemic mixture of piperidine derivative enantiomerscan be chromatographically separated using chiral stationary phases orby recrystallization by using chiral solvents.

Piperidine derivatives having keto groups can also be converted toenantiomerically pure piperidine derivatives having hydroxy groups byusing chiral reducing agents. For example, reduction using(+)-B-chlorodiisopropinocamphenylborane produces the piperidinederivative having R chirality at the carbon to which the hydroxy groupis bonded. Alternatively, by using(−)-B-chlorodiisopropinocamphenylborane produces the S enantiomer. Othersuitable chiral reducing agents are (R) and (S)-oxazaborolidine/BH₃,potassium9-O-(1,2:5,6-di-O-isopropylidine-α-D-glucofuransoyl)-9-boratabicyclo[3.3.1]nonane,(R) and (S)-B-3-pinanyl-9-borabicyclo[3.3.1]nonane, NB-enantride,lithium (R)-(+) and (S)-(−)-2,2′-dihydroxy-1,1′-binaphthyl alkoxylaluminum hydride, (R)-(+)- and(S)-(−)-2,2′-dihydroxy-6,6′-dimethylbiphenyl borane-amine complex,tris(((1S, 2S, 5R)-2-isoprophy-5-methyl-cyclohex-1-yl)methyl)aluminum,(((1R, 3R)-2,2-dimethylbicyclo[2.2.1]hept-3-yl)methyl)berylliumchloride, (R)-BINAP-ruthenium complex/H₂, and6,6′-bis(diphenylphosphino)-3,3′-dimethoxy-2,2′,4,4′-tetramethyl-1,1′-biphenyl.

When esters with hydroxyl groups have been formed, base hydrolysis canbe used to produce a carboxylic acid. Such procedures are well known andgenerally involve treatment with an inorganic base, such as, sodiumhydroxide or potassium hydroxide, in an aqueous lower alcoholic solvent,such as aqueous methanol, ethanol, isopropyl alcohol, or n-butanol. Basehydrolysis is carried out at a temperature from about room temperatureto about the solvent reflux temperature for about ½ hour to 12 hours.

In like manner, piperidine derivative precursors bearing a keto groupand having the formula:

can be reduced to piperidine derivative precursors bearing a hydroxylgroup having the formula:

The piperidine derivative precursors bearing a hydroxyl group can beconverted to the piperidine derivative having the formula:

in vitro, such as by treating the piperidine derivative precursorbearing a hydroxyl group with strong acid, as discussed above, or,alternatively, in vivo, by administering the piperidine derivativeprecursor bearing a hydroxyl group to a subject. Piperidine derivativeprecursors bearing hydroxyl groups, like piperidine derivativeprecursors bearing keto groups, can be used to treat allergic reactions,such as asthma or allergic rhinitis.

The present invention is further illustrated by the following examples.

EXAMPLES Example 1 Preparation of4-bromo-α-(4,4-dimethylisoxazolin-2-yl)toluene

A mixture of 4-bromophenylacetic acid (172 g, 0.800 mole),2-amino-2-methyl-1-propanol (115 mL, 1.20 mole), and 900 mL xylenes wererefluxed for 24 hours in an apparatus equipped with a Dean-Stark trap.The mixture was then cooled, filtered, and concentrated to afford acrystalline solid. The solid was slurried in hexanes, and filtered toafford 147 g of a white solid. The hexane filtrate was thenconcentrated, slurried with hexanes, and filtered to afford another 13 gof 4-bromo-α-(4,4-dimethylisoxazolin-2-yl)toluene as a white solid. Thecombined yield was 160 g (75%).

Example 2 Preparation of4-bromo-α,α-dimethyl-α-(4,4-dimethylisoxazolin-2-yl)toluene

A 250 mL three neck round bottomed flask was charged with 5.0 g (0.0186mole) of 4-bromo-α-(4,4-dimethylisoxazolin-2-yl)toluene, preparedaccording to Example 1, and 50 mL of dry THF under N₂. KHMDS, 27 mL(0.0279 mole, 1.5 eq), was then slowly added over 10 minutes. A colorchange to deep orange was observed. After stirring the mixture for 15minutes at room temperature, 1.16 mL (0.0186 mole, 1 equiv.) of methyliodide was added in one portion. The reaction exothermed to 46° C., andwhite solid precipitated while the solution retained a pale yellow tint.After stirring for 1 hour, another 27 mL (0.0279 mole, 1.5 equiv.) ofKHMDS was added causing the temperature of the reaction to rise from 27°to 30° C. and the color to change to orange. The reaction was stirredfor an additional 20 minutes and, thereafter, a second equivalent ofCH₃I was added. An aliquot was removed, quenched with water, andextracted with ethyl acetate. TLC analysis (4:1 hexane/ethyl acetate)showed the presence of the more polar4-bromo-α-methyl-α-(4,4-dimethylisoxazolin-2-yl)toluene (“mono adduct”).An additional 0.2 mL of CH₃I was added which turned the pale yellowsolution to white. The reaction mixture was then added to 100 mL 10%acetic acid/water along with 250 mL methylene chloride. The organiclayer was washed twice with 50 mL brine and dried with sodium sulfate.After concentration and drying at room temperature and a pressure of 0.1mm Hg overnight, 5.65 g (103%) of a yellowish solid was obtained. Thesolid was dissolved in 30 mL isopropanol and 20 mL of water was slowlyadded until an oil had formed. To the mixture, 5 mL of isopropanol wasadded with heating to dissolve all of the oil. The oil crystallized uponcooling in an ice bath, yielding 4.61 g (0.0156 mmole, 84%) of pure4-bromo-α,α-dimethyl-α-(4,4-dimethylisoxazolin-2-yl)toluene no trace ofmono adduct.

Example 3 Preparation of4-(cyclopropyl-oxo-methyl)-α,α-dimethyl-α-(4,4-dimethyloxozolin-2-yl)toluene

A solution of4-bromo-α,α-dimethyl-α-(4,4-dimethylisoxazolin-2-yl)toluene, preparedaccording to Example 2, (10.0 g. 0.0338 mole) in 400 mL THF was cooledto −78° C., n-butyllithium (16 mL, 0.042 mole) was added via syringe,and the mixture was stirred at −78° C. for 30 minutes. While keeping thetemperature below −75° C., N,N-dimethyl cyclopropylcarboxylic acid amide(11.5 g, 0.102 mole) in 30 mL THF was added dropwise, and the mixturewas stirred at −78° C. for 30 minutes. The mixture was allowed to warmto −15° C., and was quenched with water. The product was extracted withmethylene chloride, washed with saturated NaCl solution, dried overNa₂SO₄, and concentrated. The residue was cooled to 0° C., treated withminimal acetonitrile, and filtered, to afford 6.95 g of4-(cyclopropyl-oxo-methyl)-α,α-dimethyl-α-(4,4-dimethyloxozolin-2-yl)tolueneas a white solid (72%).

Example 4 Preparation of4-(4-chloro-1-oxobutyl)-α,α-dimethylphenylacetic acid

A mixture of4-(cyclopropyl-oxo-methyl)-α,α-dimethyl-α-(4,4-dimethyloxozolin-2-yl)toluene,prepared according to Example.3, (42 g, 0.15 mole), 150 mL concentratedhydrochloric acid, and 150 mL 1,4-dioxane was brought to reflux for 18hours. The mixture was extracted three times with ethyl acetate. Theorganics were washed with saturated NaCl solution, dried over MgSO₄, andconcentrated. Crude product was purified by column chromatography using240 g silica gel, and eluting with 81:14:5 hexanes/ethyl acetate/aceticacid. Cleaner fractions were combined and recrystallized from methylenechloride/hexanes to afford 27 g of4-(4-chloro-1-oxobutyl)-α,α-dimethylphenylacetic acid as a white solid(68%).

Example 5 Preparation of Methyl4-(4-chloro-1-oxobutyl)-α,α-dimethylphenylacetate

A solution of 4-(4-chloro-1-oxobutyl)-α,α-dimethylphenylacetic acid,prepared according to Example 4, (15 g, 0.056 mole) in 450 mL of aHCl-saturated methanol was refluxed for 1 hour. The mixture wasconcentrated to dryness and partitioned between ethyl acetate and water.The aqueous phase was extracted twice again with ethyl acetate. Thecombined organic phases were dried over MgSO₄ and concentrated to anoil. The oil was purified by column chromatography using 150 g of silicagel, and eluting with 11:1 hexanes/ethyl acetate. Clean fractions werecombined and concentrated to afford 13 g of methyl4-(4-chloro-1-oxobutyl)-α,α-dimethylphenylacetate as a clear, colorlessoil (82%).

Example 6 Preparation of Methyl4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylphenylacetate

A solution of 12.6 g of methyl4-(4-chloro-1-oxobutyl)-α,α-dimethylphenylacetate in 500 mL of toluenein a one liter three neck flask with mechanical stirring was added 8.8 gof 4-(α,α-diphenyl)piperidinemethanol and 23 g of K₂CO₃ and the mixturewas refluxed for 7 hr. The cooled reaction mixture was then filtered andconcentrated in vacuo. The residue was dissolved in Et₂O and treatedwith excess ethereal HCl. The mixture was then concentrated to a solid.The solid was treated with EtOAc and collected by filtration. Theproduct was then partitioned between EtOAc and 2N Na₂CO₃. The organicswere dried over MgSO₄, filtered, and concentrated in vacuo to affordmethyl4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylphenylacetate.

Example 7 Preparation of Methyl4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylacetate

A solution of 13.5 g of methyl4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylphenylacetatein 250 mL of CH₃OH is cooled in an ice CH₃OH bath, and 1.8 g of NaBH₄was added in portions. After 1 hr, the mixture was concentrated to asolid. The residue was partitioned between EtOAc and saturated aqueousNaHCO₃. The aqueous portion was extracted with EtOAc. The combinedorganics were washed with saturated aqueous NaCl, dried over MgSO₄,filtered, and concentrated in vacuo to afford methyl4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylacetateas a foam.

Example 8 Preparation of4-[4-[4-Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylaceticAcid

To a solution of 9.5 g ofmethyl-4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylacetatein 300 mL of CH₃OH and 150 mL of H₂O, was added 10 g of NaOH. Themixture was refluxed for 1 hr, then cooled. The CH₃OH was removed invacuo. The concentrate was diluted with H₂O and CHCl₃, and the pH isadjusted to approximately 5.5 to 6.0. The phases were separated, and theaqueous phase was extracted with CHCl₃. The combined organics were driedover MgSO₄, filtered, and stripped to afford crude product.

The crude product was dissolved in CH₂Cl₂ and chromatographed on DavisilGrade 633 SiO₂ eluting with a gradient of CHCl₃, to 10% CH₃OH in CHCl₃,to 25% CH₃OH in CHCl₃. The product containing fractions wereconcentrated to afford4-[4-[4-hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylaceticacid.

Example 9 Preparation of Methyl4-[4-[4-(Bis(4-methylphenyl)hydroxymethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylphenylacetate

To a solution of 6.4 g (0.017 mol) of methyl4-(4-chloro-1-oxobutyl)-α,α-dimethylphenylacetate in 500 mL of toluenein a one liter round bottom flask equipped with a mechanical stirrer wasadded 5.1 g (0.017 mol) of4-(α,α-bis(4-methylphenyl)-piperidinemethanol, followed by 11.8 g (0.086mol) of solid potassium carbonate. The solution was heated to reflux for24 hr. After cooling, the mixture was filtered, and the toluene wasremoved in vacuo. The residue was partitioned between ethyl acetate and2 N sodium carbonate solution. The aqueous layer was extracted twicewith ethyl acetate, the combined organic layers were dried with sodiumsulfate, and the ethyl acetate was removed in vacuo to provide methyl4-[4-[4-(bis(4-methylphenyl)hydroxymethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylphenylacetate.

Example 10 Preparation of Methyl4-[4-[4-(Bis(4-Methylphenyl)hydroxymethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylacetate

To a −10° C. solution of 6.8 g (0.013 mol) of methyl4-[4-[4-(bis(4-methylphenyl)hydroxymethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylphenylacetatein 150 mL of methanol in a 500 mL round bottom flask equipped with amechanical stirrer was slowly added 0.86 g (0.023 mol) of sodiumborohydride, and the reaction was stirred for 2 hr. The methanol wasremoved in vacuo, and the residue was partitioned between ethyl acetateand aqueous sodium bicarbonate solution. The aqueous layer was extractedwith ethyl acetate, the combined organic layers were dried with sodiumsulfate, and the ethyl acetate was removed in vacuo to provide crudeproduct. The resultant material was purified by column chromatography(Davisil grade 633 silica gel, packed in methylene chloride, materialapplied in chloroform, and eluted with a gradient of 2% methanol tomethylene chloride to 5% methanol to methylene chloride) to affordmethyl4-[4-[4-(bis(4-methylphenyl)hydroxymethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylacetate.

Example 11 Preparation of4-[4-[4-(Bis(4-methylphenyl)hydroxymethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylaceticAcid

To 350 mL of methanol in a 1 L round bottom flask equipped with amechanical stirrer was added 5.3 g (9.8 mmol) of methyl4-[4-[4-(bis(4-methylphenyl)hydroxymethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylacetae,5.1 g (0.13 mol) of solid sodium hydroxide, and 100 mL of water. Themixture was heated to reflux for 3 hr. After cooling, the methanol wasremoved in vacuo, and 6 N hydrochloric acid was added dropwise until thesolution was no longer basic (pH=7). The solution was extracted threetimes with ethyl acetate. The organic layers were combined, andprecipitation is induced. The solid was washed with ether to provide4-[4-[4-(bis(4-methylphenyl)hydroxymethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylaceticacid, as the dihydrate.

Example 12 Preparation of4-(1-Hydroxy-4-chlorobutyl)-α,α-dimethylphenylacetic acid

To a solution of 50 mg of4-(4-chloro-1-oxobutyl)-α,α-dimethylphenylacetic acid in 3 mL ofmethanol was added 50 mg of NaBH₄. The mixture was stirred for 30minutes, acidified with 2N HCl, and the methanol was removed in vacuo.The concentrate was extracted with EtOAc. The organics were dried overNa₂SO₄, filtered, and concentrated to afford4-(1-hydroxy-4-chlorobutyl)-α,α-dimethylphenylacetic acid.

Example 13 Preparation of4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylphenylaceticacid

A mixture of 800 mg of 4-(4-chloro-1-oxobutyl)-α,α-dimethylphenylaceticacid, 800 mg of 4-(α,α-diphenyl)piperidinemethanol, and 2.4 g of K₂CO₃in 25 mL of toluene was stirred for 48 hours at room temperature. Themixture was concentrated in vacuo. The residue was treated with EtOAc.filtered, and concentrated to afford4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylphenylaceticacid.

Example 14 Preparation of4-[4-[4-Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylaceticAcid

A mixture of4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylphenylaceticacid, and 300 mg of NaBH₄ in 25 mL of CH₃OH was stirred overnight atroom temperature. The mixture was then concentrated in vacuo. Theresidue was partitioned between EtOAc and H₂O. The aqueous portion wastreated with concentrated HCl until pH 6, then extracted with EtOAc. Theorganics were concentrated in vacuo. The residue was dissolved in EtOAc,filtered, and concentrated in vacuo to an oil. The oil was dissolved inCH₃OH and concentrated to a solid. The solid was slurried with EtOAc,filtered, and rinsed with EtOAc to afford4-[4-[4-hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylaceticacid.

Although the invention has been described in detail for the purpose ofillustration, it is understood that such detail is solely for thatpurpose, and variations can be made therein by those skilled in the artwithout departing from the spirit and scope of the invention which isdefined by the following claims.

1. A process of preparing a piperidine derivative compound of theformula:

wherein n is 0 or 1; R¹ is hydrogen or hydroxy; R² is hydrogen; or, whenn is 0, R¹ and R² taken together form a second bond between the carbonatoms bearing R¹ and R², provided that when n is 1, R¹ and R² are eachhydrogen; R³ is —COOH or —COOR⁴; R⁴ is an alkyl or aryl moiety; A, B,and D are the substituents of their rings, each of which may bedifferent or the same, and are selected from the group consisting ofhydrogen, halogens, alkyl, hydroxy, alkoxy, and other sybstituents; saidprocess comprising: providing a regioisomer of the following formula:

wherein Z is

m is an integer from 1 to 6; Q is O; Y is selected from the groupconsisting of O, S, and NR⁵; R⁶ and R⁷ are the same or different and areselected from the group consisting of hydrogen, an alkyl moiety, an arylmoiety, OR⁸, SR⁸, and NR⁸R⁹; and R⁵, R⁸, and R⁹ are the same ordifferent and are selected from the group consisting of hydrogen, analkyl moiety, and an aryl moiety and converting the regioisomer to thepiperidine derivative compound with a piperidine compound.
 2. A processaccording to claim 1, wherein said providing the regioisomer comprises:acylating an α,α-disubstituted-methylbenzene derivative having theformula:

wherein X¹ is a halogen, trialkyl or triaryl tin, trialkyl or triarylborate, trialkyl silicon, alkylbalo silicon, a substituted sulfonicester, or substituents useful in organometallic coupling reactions witha compound having the formula:

wherein X² is a halogen; an alkali metal oxide; a moiety having theformula —OR¹⁰; a moiety having the formula —SR¹⁰; or an amine; and R¹⁰is selected from the group consisting of hydrogen, an alkyl moiety, andan aryl moiety under conditions effective to produce the regioisomer. 3.A process according to claim 2 further comprising: reacting anα,α-diunsubstituted-metbylbenzene derivative having the formula:

with a methylating agent under conditions effective to produce theα-α-disubstituted-methylbenzene derivative.
 4. A process according toclaim 3, wherein Z has the formula:

and further comprising reacting an α,α-diunsubstituted benzylic acidderivative having the formula:

with an aminoalkyl derivative having the formula:H₂N—(CR⁶R⁷)_(m)-Q-H under conditions effective to produce theα,α-diunsubstituted-methylbenzene derivative.
 5. A process according toclaim 2, wherein Z has the formula:

and further comprising: reacting an α,α-disubstituted benzylic acidderivative having the formula:

with an aminoalkyl derivative having the formula:H₂N—(CR⁶R⁷)_(m)-Q-H under conditions effective to produce theα,α-disubstituted-methylbenzene derivative.
 6. A process according toclaim 1, wherein said providing the regioisomer comprises: reacting a4-(α,α-disubstituted)-toluic acid derivative having the formula:

wherein X² is hydrogen; a halogen; an alkali metal oxide; a moietyhaving the formula —OR¹⁰; a moiety having the formula —SR¹⁰; or anamine; and R¹⁰ is selected from the group consisting of hydrogen, analkyl moiety, and an aryl moiety with a compound having the formula:

wherein X¹ is a halogen, trialkyl or triaryl tin, trialkyl or triarylborate, trialkyl silicon, alkylhalo silicon, a substituted sulfonicester, or substituents useful in organometallic coupling reactions underconditions effective to produce the regioisomer.
 7. A process accordingto claim 6, further comprising: reacting a4-(α,α-diunsubstituted)-toluic acid derivative having the formula:

with a methylating agent under conditions effective to produce the4-(α,α-disubstituted)-toluic acid derivative.
 8. A process according toclaim 7, wherein Z has the formula:

and further comprising: reacting a4-(α-carboxy-α,α-diunsubstituted)-toluic acid derivative having theformula:

with an aminoalkyl derivative having the formula:H₂N—(CR⁶R⁷)_(m)-Q-H under conditions effective to produce the4-(α,α-diunsubstituted)-toluic acid derivative.
 9. A process accordingto claim 6, wherein Z has the formula:

and further comprising: reacting a4-(α-carboxy-α,α-disubstituted)-toluic acid derivative having theformula:

with an aminoalkyl derivative having the formula:H₂N—(CR⁶R⁷)_(m)-Q-H under conditions effective to produce the4-(α,α-disubstituted)-toluic acid derivative.
 10. A process according toclaim 1, wherein said providing the regioisomer comprises: providing anα,α-diunsubstituted regioisomer precursor having the formula:

and methylating the α,α-diunsubstituted regioisomer precursor underconditions effective to produce the regioisomer.
 11. A process accordingto claim 10, wherein said providing the α,α-diunsubstituted regioisomerprecursor comprises: acylating an α,α-diunsubstituted-methylbenzenederivative having the formula:

wherein X¹ is a halogen, trialkyl or triaryl tin, trialkyl or triarylborate, trialkyl silicon, alkylhalo silicon, a substituted sulfonicester, or substituents useful in organometallic coupling reactions witha compound having the formula:

wherein X² is a halogen; an alkali metal oxide; a moiety having theformula —OR¹⁰; a moiety having the formula —SR¹⁰; or an amine; and R¹⁰is selected from the group consisting of hydrogen, an alkyl moiety, andan aryl moiety under conditions effective to produce theα,α-diunsubstituted regioisomer precursor.
 12. A process according toclaim 10, wherein said providing the α,α-diunsubstituted regioisomerprecursor comprises: reacting a 4-(α,α-diunsubstituted)-toluic acidderivative having the formula:

wherein X² is hydrogen; a halogen; an alkali metal oxide; a moietyhaving the formula —OR¹⁰; a moiety having the formula —SR¹⁰; or anamine; and R¹⁰ is selected from the group consisting of hydrogen, analkyl moiety, and an aryl moiety with a compound having the formula:

wherein X¹ is a halogen, trialkyl or triaryl tin, trialkyl or triarylborate, trialkyl silicon, alkylhalo silicon, a substituted sulfonicester, or substituents useful in organometallic coupling reactions underconditions effective to produce the α,α-diunsubstituted regioisomerprecursor.
 13. A process according to claim 1, further comprising:reducing the piperidine derivative compound under conditions effectiveto form a hydroxylated piperidine derivative compound of the formula:


14. A process according to claim 1, wherein m is an integer from 2 to 4.15. A process of preparing a piperidine derivative compound of theformula:

wherein n is 0 or 1; R¹ is hydrogen or hydroxy; R² is hydrogen; or, whenn is 0, R¹ and R² taken together form a second bond between the carbonatoms bearing R¹ and R², provided that when n is 1, R¹ and R² are eachhydrogen; R³ is —COOH or —COOR⁴; R⁴ is an alkyl or aryl moiety; A, B,and D are the substituents of their rings, each of which may bedifferent or the same, and are selected from the group consisting ofhydrogen, halogens, alkyl, hydroxy, alkoxy, and other substituents; saidprocess comprising: providing a regioisomer of the following formula:

wherein Z is

m is an integer from 1 to 6; Q is S; Y is selected from the groupconsisting of O, S, and NR⁵; R⁶ and R⁷ are the same or different and areselected from the group consisting of hydrogen, an alkyl moiety, an arylmoiety, OR⁸, SR⁸, and NR⁸R⁹; and R⁵, R⁸, and R⁹ are the same ordifferent and are selected from the group consisting of hydrogen, analkyl moiety, and an aryl moiety and converting the regioisomer to thepiperidine derivative compound with a piperidine compound.
 16. A processaccording to claim 15, wherein said providing the regioisomer comprises:acylating an α,α-disubstituted-methylbenzene derivative having theformula:

wherein X¹ is a halogen, trialkyl or triatyl tin, trialkyl or triarylborate, trialkyl silicon, alkylhalo silicon, a substituted sulfonicester, or substituents useful in organometallic coupling reactions witha compound having the formula:

wherein X² is a halogen; an alkali metal oxide; a moiety having theformula —OR¹⁰; a moiety having the formula —SR¹⁰; or an amine; and R¹⁰is selected from the group consisting of hydrogen, an alkyl moiety, andan aryl moiety under conditions effective to produce the regioisomer.17. A process according to claim 16 further comprising: reacting anα,α-diunsubstituted-methylbenzene derivative having the formula:

with a methylating agent under conditions effective to produce theα-α-disubstituted-methylbenzene derivative.
 18. A process according toclaim 17, wherein Z has the formula:

and further comprising reacting an α,α-diunsubstituted benzylic acidderivative having the formula:

with an aminoalkyl derivative having the formula:H₂N—(CR⁶R⁷)_(m)-Q-H under conditions effective to produce theα,α-diunsubstituted-metbylbenzene derivative.
 19. A process according toclaim 16, wherein Z has the formula:

and further comprising: reacting an α,α-disubstituted benzylic acidderivative having the formula:

with an aminoalkyl derivative having the formula:  H₂N—(CR⁶R⁷)_(m)-Q-Hunder conditions effective to produce theα,α-disubstituted-methylbenzene derivative.
 20. A process according toclaim 15, wherein said providing the regioisomer comprises: reacting a4-(α,α-disubstituted)-toluic acid derivative having the formula:

wherein X² is hydrogen; a halogen; an alkali metal oxide; a moietyhaving the formula —OR¹⁰; a moiety having the formula —SR¹⁰; or anamine; and R¹⁰ is selected from the group consisting of hydrogen, analkyl moiety, and an aryl moiety with a compound having the formula:

wherein X¹ is a halogen, trialkyl or triaryl tin, trialkyl or triarylborate, trialkyl silicon, alkylhalo silicon, a substituted sulfonicester, or substituents useful in organometallic coupling reactions underconditions effective to produce the regioisomer.
 21. A process accordingto claim 20, further comprising: reacting a4-(α,α-diunsubstituted)-toluic acid derivative having the formula:

with a methylating agent under conditions effective to produce the4-(α,α-disubstituted)-toluic acid derivative.
 22. A process according toclaim 21, wherein Z has the formula:

and further comprising: reacting a4-(α-carboxy-α,α-diunsubstituted)-toluic acid derivative having theformula:

with an aminoalkyl derivative having the formula:H₂N—(CR⁶R⁷)_(m)-Q-H under conditions effective to produce the4-(α,α-diunsubstituted)-toluic acid derivative.
 23. A process accordingto claim 20, wherein Z has the formula:

and further comprising: reacting a4-(α-carboxy-α,α-disubstituted)-toluic acid derivative having theformula:

with an aminoalkyl derivative having the formula:H₂N—(CR⁶R⁷)_(m)-Q-H under conditions effective to produce the4-(α,α-disubstituted)-toluic acid derivative.
 24. A process according toclaim 15, wherein said providing the regioisomer comprises: providing anα,α-diunsubstituted regioisomer precursor having the formula:

and methylating the α,α-diunsubstituted regioisomer precursor underconditions effective to produce the regioisomer.
 25. A process accordingto claim 24, wherein said providing the α,α-diunsubstituted regioisomerprecursor comprises: acylating an α,α-diunsubstituted-methylbenzenederivative having the formula:

wherein X¹ is a halogen, trialkyl or triaryl tin, trialkyl or triarylborate, trialkyl silicon, alkylhalo silicon, a substituted sulfonicester, or substituents useful in organometallic coupling reactions witha compound having the formula:

wherein X² is a halogen; an alkali metal oxide; a moiety having theformula —OR¹⁰; a moiety having the formula —SR¹⁰; or an amine; and R¹⁰is selected from the group consisting of hydrogen, an alkyl moiety, andan aryl moiety under conditions effective to produce theα,α-diunsubstituted regioisomer precursor.
 26. A process according toclaim 24, wherein said providing the α,α-diunsubstituted regioisomerprecursor comprises: reacting a 4-(α,α-diunsubstituted)-toluic acidderivative having the formula:

wherein X² is hydrogen; a halogen; an alkali metal oxide; a moietyhaving the formula —OR¹⁰; a moiety having the formula —SR¹⁰; or anamine; and R¹⁰ is selected from the group consisting of hydrogen, analkyl moiety, and an aryl moiety with a compound having the formula:

wherein X¹ is a halogen, trialkyl or triaryl tin, trialkyl or triarylborate, trialkyl silicon, alkylhalo silicon, a substituted sulfonicester, or substituents useful in organometallic coupling reactions underconditions effective to produce the α,α-diunsubstituted regioisomerprecursor.
 27. A process according to claim 15, further comprising:reducing the piperidine derivative compound under conditions effectiveto form a hydroxylated piperidine derivative compound of the formula:


28. A process according to claim 15, wherein m is an integer from 2 to4.
 29. A process of preparing a piperidine derivative compound of theformula:

wherein n is 0 or 1; R¹ is hydrogen or hydroxy; R² is hydrogen; or, whenn is 0, R¹ and R² taken together form a second bond between the carbonatoms bearing R¹ and R², provided that when n is 1, R¹ and R² are eachhydrogen; R³ is —COOH or —COOR⁴; R⁴ is an alkyl or aryl moiety; A, B,and D are the substituents of their rings, each of which may bedifferent or the same, and are selected from the group consisting ofhydrogen, halogens, alkyl, hydroxy, alkoxy, and other substituents; saidprocess comprising: providing a regioisomer of the following formula:

wherein Z is

m is an integer from 1 to 6; Q is NR⁵; Y is selected from the groupconsisting of O, S, and NR⁵; R⁶ and R⁷ are the same or different and areselected from the group consisting of hydrogen, an alkyl moiety, an arylmoiety, OR⁸, SR⁸, and NR⁸R⁹; and R⁵, R⁸, and R⁹ are the same ordifferent and are selected from the group consisting of hydrogen, analkyl moiety, and an aryl moiety and converting the regioisomer to thepiperidine derivative compound with a piperidine compound.
 30. A processaccording to claim 29, wherein said providing the regioisomer comprises:acylating an α,α-disubstituted-methylbenzene derivative having theformula:

wherein X¹ is a halogen, trialkyl or triaryl tin, trialkyl or triarylborate, trialkyl silicon, alkylhalo silicon, a substituted sulfonicester, or substituents useful in organometallic coupling reactions witha compound having the formula:

wherein X² is a halogen; an alkali metal oxide; a moiety having theformula —OR¹⁰; a moiety having the formula —SR¹⁰; or an amine; and R¹⁰is selected from the group consisting of hydrogen, an alkyl moiety, andan aryl moiety under conditions effective to produce the regioisomer.31. A process according to claim 30 further comprising: reacting anα,α-diunsubstituted-methylbenzene derivative having the formula:

with a methylating agent under conditions effective to produce theα-α-disubstituted-methylbenzene derivative.
 32. A process according toclaim 31, wherein Z has the formula:

and further comprising reacting an α,α-diunsubstituted benzylic acidderivative having the formula:

with an aminoalkyl derivative having the formula:H₂N—(CR⁶R⁷)_(m)-Q-H under conditions effective to produce theα,α-diunsubstituted-methylbenzene derivative.
 33. A process according toclaim 30, wherein Z has the formula:

and further comprising: reacting an α,α-disubstituted benzylic acidderivative having the formula:

with an aminoalkyl derivative having the formula:  H₂N—(CR⁶R⁷)_(m)-Q-Hunder conditions effective to produce theα,α-disubstituted-methylbenzene derivative.
 34. A process according toclaim 29, wherein said providing the regioisomer comprises: reacting a4-(α,α-disubstituted)-toluic acid derivative having the formula:

wherein X² is hydrogen; a halogen; an alkali metal oxide; a moietyhaving the formula —OR¹⁰; a moiety having the formula —SR¹⁰; or anamine; and R¹⁰ is selected from the group consisting of hydrogen, analkyl moiety, and an aryl moiety with a compound having the formula:

wherein X¹ is a halogen, trialkyl or triaryl tin, trialkyl or triarylborate, trialkyl silicon, alkylhalo silicon, a substituted sulfonicester, or substituents useful in organometallic coupling reactions underconditions effective to produce the regioisomer.
 35. A process accordingto claim 34, further comprising: reacting a4-(α,α-diunsubstituted)-toluic acid derivative having the formula:

with a methylating agent under conditions effective to produce the4-(α,α-disubstituted)-toluic acid derivative.
 36. A process according toclaim 35, wherein Z has the formula:

and further comprising: reacting a4-(α-carboxy-α,α-diunsubstituted)-toluic acid derivative having theformula:

with an aminoalkyl derivative having the formula:H₂N—(CR⁶R⁷)_(m)-Q-H under conditions effective to produce the4-(α,α-diunsubstituted)-toluic acid derivative.
 37. A process accordingto claim 34, wherein Z has the formula:

and further comprising: reacting a4-(α-carboxy-α,α-disubstitiuted)-toluic acid derivative having theformula:

with an aminoalkyl derivative having the formula:H₂N—(CR⁶R⁷)_(m)-Q-H under conditions effective to produce the4-(α,α-disubstituted)-toluic acid derivative.
 38. A process according toclaim 29, wherein said providing the regioisomer comprises: providing anα,α-diunsubstituted regioisomer precursor having the formula:

and methylating the α,α-diunsubstituted regioisomer precursor underconditions effective to produce the regioisomer.
 39. A process accordingto claim 38, wherein said providing the α,α-diunsubstituted regioisomerprecursor comprises: acylating an α,α-diunsubstituted-methylbenzenederivative having the formula:

wherein X¹ is a halogen, trialkyl or triaryl tin, trialkyl or triarylborate, trialkyl silicon, alkylhalo silicon, a substituted sulfonicester, or substituents useful in organometallic coupling reactions witha compound having the formula:

wherein X² is a halogen; an alkali metal oxide; a moiety having theformula —OR¹⁰; a moiety having the formula —SR¹⁰; or an amine; and R¹⁰is selected from the group consisting of hydrogen, an alkyl moiety; andan aryl moiety under conditions effective to produce theα,α-diunsubstituted regioisomer precursor.
 40. A process according toclaim 38, wherein said providing the α,α-diunsubstituted regioisomerprecursor comprises: reacting a 4-(α,α-diunsubstituted)-toluic acidderivative having the formula:

wherein X² is hydrogen; a halogen; an alkali metal oxide; a moietyhaving the formula —OR¹⁰; a moiety having the formula —SR¹⁰; or anamine; and R¹⁰ is selected from the group consisting of hydrogen, analkyl moiety, and an aryl moiety with a compound having the formula:

wherein X¹ is a halogen, trialkyl or triaryl tin, trialkyl or triarylborate, trialkyl silicon, alkylhalo silicon, a substituted sulfonicester, or substituents useful in organometallic coupling reactions underconditions effective to produce the α,α-diunsubstituted regioisomerprecursor.
 41. A process according to claim 29, further comprising:reducing the piperidine derivative compound under conditions effectiveto form a hydroxylated piperidine derivative compound of the formula:


42. A process according to claim 29, wherein m is an integer from 2 to4.
 43. A process according to claim 29, wherein R⁵ is hydrogen.
 44. Aprocess according to claim 29, wherein R⁵ is a branched or unbranchedC1-C7 alkyl group.
 45. A process according to claim 29, wherein R⁵ is anaryl or heteroaryl group.